Depressive symptoms are very common in the elderly, especially among women, and have been linked with cognitive and physical disability, although the nature and direction of this association, including the causal interpretation, remains controversial. We propose to investigate how depressive symptoms among elderly women are associated with cognitive and functional decline over the long term. Assessing depressive symptoms at only one timepoint (as has been done in almost all previous studies) is inadequate because depressive symptoms are commonly variable over time, and because the cumulative impact of depressive symptoms may take time to manifest itself. To best investigate the full impact of a chronic disease such as depression, we need to study its long-term course, in accord with the 2008 NIMH Strategic Plan to chart trajectories of mental health symptoms and with research priorities expressed in PA-07-163. We also propose to investigate several targeted biological mechanisms that may underlie the association between depressive symptoms and cognitive and functional decline. Few studies, if any, have comprehensively investigated these mechanisms and yet, their discovery could yield important opportunities for prevention and treatment, not to mention an essential understanding of the biology of depression. Finally we propose to study the effects of depressive symptoms in the oldest old. Little information exists on the prevalence and severity of depressive symptoms and their associated health outcomes in this population, typically defined as elders aged =85 years, and the fastest growing segment of the U.S. population. Based on our preliminary data, substantial depressive symptoms are common in this population, affecting 15-25% of the oldest old. Our aims will be addressed from ongoing prospective study of over 10,000 elderly women (including 3800 oldest old) who enrolled at age = 65 years and who have been rigorously followed for almost 20 years. In an extremely cost-effective approach, we will determine the long-term course of depressive symptoms and how these symptoms are associated with the development of cognitive and functional decline. In addition, we will determine if the association between depressive symptoms and these outcomes is partially explained by key biological pathways such as inflammation, sleep quality, cardiovascular disease and blood [unreadable]-amyloid level. Knowledge gained from this proposal will be both novel and critical for understanding the impact of depressive symptoms over the long term on health outcomes in older women including the oldest old. It will shed important insights on both the clinical need for monitoring/treating the elderly with depressive symptoms and on the biological mechanisms that may link depression to cognitive impairment and disability. PUBLIC HEALTH RELEVANCE: Knowledge gained from this proposal will be both novel and critical for understanding the impact of geriatric depressive symptoms on age-related health outcomes in older women including the oldest old. It will shed important insights on both the clinical need for monitoring/treating the elderly with depressive symptoms and on the biological mechanisms that may link depression to cognitive and functional decline.